Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A procedure is described for the rapid preparation of nerve ending particles (synaptosomes) from 11 regions of one rat brain. The synaptosomal fractions have been characterized by electron microscopy and determination of four marker enzymes, i.e., glutamate decarboxylase (GAD), acetylcholinesterase, succinate dehydrogenase, and glycerol 3-phosphate dehydrogenase. Comparison with a much lengthier standard (Ficoll-sucrose) preparation showed that the synaptosomal yield of the new procedure was substantially better as judged by both morphological evaluation and protein recovery. The improved synaptosome preparation was used for determination of regional gamma-aminobutyric acid (GABA) levels in synaptosomal fractions. The postmortem increase in GABA level during removal and dissection of brain tissue and homogenization and fractionation procedures could be minimized by rapid processing of the tissue at low temperatures and inclusion of the GAD inhibitor 3-mercaptopropionic acid (3-MP; 1 mM) in the homogenizing medium. The addition of GABA (0.2 mM) to the homogenizing medium did not alter the GABA levels in the synaptosomes, indicating that no significant redistribution of GABA occurred during subcellular fractionation in sodium-free media. Synaptosomal GABA levels determined in the 11 rat brain areas showed the same regional distribution as the GABA-synthesizing enzyme GAD. On the basis of these findings, it was suggested that the synaptosome preparation could be used to evaluate the in vivo effects of drugs on nerve terminal GABA. Treatment of rats with a convulsant dose of 3-MP (50 mg/kg i.p.) 3 min before decapitation significantly lowered synaptosomal GABA levels in olfactory bulb, hippocampus, thalamus, tectum, and cerebellum. The 3-MP-induced seizures and reduction of GABA levels could be prevented by administration of valproic acid (200 mg/kg i.p.) 15 min before the 3-MP injection. The data indicate that the improved synaptosome preparation offers a convenient method of preparing highly purified synaptosomes from a large number of small tissue samples and can provide useful information on the in vivo effects of drugs on regional GABA levels in nerve terminals.
 ...
PMID:Improved method for isolating synaptosomes from 11 regions of one rat brain: electron microscopic and biochemical characterization and use in the study of drug effects on nerve terminal gamma-aminobutyric acid in vivo. 392 10

Dipiperidinoethane (DPE) administration produces seizures and CNS lesions. Here we elucidate the cholinergic origin of DPE toxicity. DPE is both an acetylcholinesterase (AChE) inhibitor and a muscarinic antagonist. This dual action negates most of the toxic effects of the compound in vivo. The neurotoxicity is believed to arise from oxidative conversion to DPE-N-oxide, which selectively inhibits AChE. Cytotoxicity does not involve muscarinic neurons, since binding parameters were unchanged following in vivo exposure.
 ...
PMID:Neurotoxicity of dipiperidinoethane due to in vivo conversion to a selective cholinesterase inhibitor. 398 60

The acute effects of diisopropylfluorophosphate (DFP) were assessed in DBA/2Ibg, C57BL/6Ibg and C3H/2Ibg mice. The DFP was administered by intraperitoneal injection in saline. Brain acetylcholinesterase (AChE) activity was maximally inhibited within 5 min after injection. All mice showed signs of organophosphate intoxication including salivation, lacrimation, diarrhea, respiratory distress, tremor and, at high doses, seizures. The C57BL mice were most susceptible to these effects of DFP. The LD50 values for DFP were 8.0, 7.6, and 6.8 mg/kg for male DBA, C3H, and C57BL mice, respectively. The LD50 values for females were nearly the same. Body temperature and brain AChE activity decreased in a dose-dependent manner following injections of DFP of 3.17, 4.22, 5.28, and 6.33 mg/kg. Maximum temperature depression occurred 2 hours after DFP administration; by 24 hours temperatures had returned to normal except for C57BL mice treated with the highest dose of DFP. The C57BL strain was most susceptible to the DFP-induced hypothermia, the C3H strain was the most resistant, and the DBA strain was intermediate. Maximum temperature depression and residual AChE activity, as measured 24 hours after injection, were linearly related. These strain differences do not seem to be explained easily by a differential inhibition of AChE activity.
 ...
PMID:Genetically determined differences in acute responses to diisopropylfluorophosphate. 399 71

The kindling phenomenon was produced after chronic electrostimulation of the cat amygdala. The duration and intensity of petit mal and grand mal were recorded. The M-cholinomimetic arecoline (0.3 mg/kg), the acetylcholinesterase inhibitor galanthamine (1-3 mg/kg) and the N-cholinergic blockers eterofen (5-10 mg/kg) and ganglerone (035-3.5 mg/kg) intraperitoneally decreased or abolished the kindling phenomenon. Combination of M-cholinomimetics with N-blockers facilitated the anticonvulsant effects. Nicotine (0.5 mg/kg) and the M-cholinergic blocker methylbenactyzine (0.5-1 mg/kg) as well as combination of methylbenactyzine with galanthamine, on the contrary, facilitated and aggravated seizures in cats. In the authors' opinion, the M- and N-cholinergic mechanisms are involved in formation of the kindling phenomenon. It is suggested that N-cholinergic blockers or their combinations with M-cholinomimetics may be used as anticonvulsants.
 ...
PMID:[Participation of m- and n-cholinergic mechanisms in the development of the kindling phenomenon of the amygdala in cats]. 400 13

Male juvenile baboons, trained on a match-to-sample operant discrimination task, were given acute intramuscular injections of soman (methyl pinacolyl phosphonofluoridate) at 1.0, 2.0, 3.0, 4.0, and 5.0 micrograms/kg. The different doses were given in a mixed order just before a behavioral test session. Just prior to administration of each soman dose and immediately following the 2-hr behavioral test session, a sample of blood (0.5 ml) was drawn from the baboon and analyzed for inhibition of acetylcholinesterase activity. Thereafter, blood sampling was accomplished at weekly intervals and soman was administered again only when whole blood acetylcholinesterase reached at least 80% of pre-soman control level. Behavioral effects of soman included a slowing of response times, a decrease in extra inconsequential responses, a decrease in responsiveness to the visual stimuli and an increase in errors. These effects were observed when acetylcholinesterase (AChE) levels fell to 25 mumoles/hr/ml blood or less. The threshold dose for behavioral effects was very close to the dose of soman which induced seizures.
 ...
PMID:Acute soman effects in the juvenile baboon: effects on a match-to-sample discrimination task and on total blood acetylcholinesterase. 402 28

Rats were trained to press a lever under a multiple fixed-ratio 25 fixed-interval 50-second (FR25 FI50-sec) schedule of food reinforcement. Soman, 70-90 micrograms/kg, s.c., suppressed response rates in both components, with a slightly greater effect in the FI schedule. The pattern of responding under the FI schedule, however, was maintained until lever-pressing was nearly completely suppressed. At the highest doses, soman occasionally caused tremors or mild tonic seizures with hindlimb abduction. The suppression of response rate was correlated with inhibition of acetylcholinesterase (AChE) in all brain regions examined: cortex, striatum, hippocampus, hypothalamus and brainstem. Cortical AChE was inhibited to the highest degree, while striatal AChE was most resistant to inhibition by soman.
 ...
PMID:Effect of soman on schedule-controlled behavior and brain acetylcholinesterase in rats. 407 56

Juvenile male baboons were trained to perform a match-to-sample discrimination task; effects of repeated sublethal exposure to the organophosphate nerve gas, soman, upon task performance were then explored. Both acute and subchronic exposure schedules were employed, and soman potency was verified by assay of soman-induced inhibition of acetylcholinesterase activity in whole blood, plasma, and erythrocytes. A characteristic profile of behavioral effects encompassing immediate, persistent, and delayed effects was observed. Immediate dose-related effects of soman included: increases in mean session response time, increases in errors, and decreases in extra responses. Seizures were also observed at the highest dose of soman employed (5 micrograms/kg). The increase in mean session response time was due to intermittent lapses in responding to stimuli (attentional deficits). Both the attentional deficits and intermittent generalized seizures were also persistent effects, with both occurring randomly after acute exposure to 5 micrograms/kg soman. Preliminary evidence suggests that occurrence of attentional deficits was associated with the occurrence of generalized and/or focal seizures; and that these effects may reflect irreversible lesions which become more threatening to the animal with increasing time. An additional, delayed effect was a sudden marked increase in the incidence of extra inconsequential responses which occurred several weeks after cessation of soman exposures.
 ...
PMID:Neurobehavioral effects of repeated sublethal soman in primates. 408 Jul 70

The (14C)-2-deoxyglucose procedure was used to determine the effects of the potent acetylcholinesterase inhibitor Soman on regional metabolism in the brain. Groups of rats were given 112 micrograms/kg Soman, 84 micrograms/kg Soman, or saline i.m., and 15 min later the (14C)-2-deoxyglucose mapping procedure was initiated. All animals given 112 micrograms/kg Soman and 2 of 6 given 84 micrograms/kg Soman developed seizures that continued throughout the mapping procedure. Very high rates of glucose use occurred in most of the brain regions studied during seizures. The most striking increases occurred in substantia nigra, septum, outer layer of dentate gyrus of the hippocampus, hippocampal body, frontal cortex, caudate, ventral thalamus, parietal cortex, medial geniculate and interpeduncular nucleus. Only the inferior colliculus, superior olivary nucleus and lateral habenula were unaffected by the seizures. The mid layers of cerebral cortex rostral to superior colliculus showed marked reductions in glucose use which may represent inhibition of neuronal activity or functional failure from depleted energy reserves. The animals given 84 micrograms/kg i.m. that did not have seizures had regional glucose use patterns similar to the controls. The results indicate that the brain damage observed by others in Soman treated rats may be in part due to the excessive neuronal stimulation that occurs during the prolonged Soman-induced seizure.
 ...
PMID:Brain regional glucose use during Soman-induced seizures. 668 61

Kainic acid (KA) was injected into the amygdala (AM) complex of the rat and its effect on the cholinergic enzymes, choline acetyltransferase (CAT) and acetylcholinesterase (AChE), and the binding of the muscarinic ligand, [3H]quinuclidinyl-benzilate (QNB) and the nicotinic ligand [125I]alpha-bungarotoxin (aBuTX) was investigated. Ka produced a loss of approximately 35% of the CAT activity in the AM. However, no effect on AChE activity was observed. A 30--50% decrease in the number of muscarinic and nicotinic receptor sites was also found. CAT, AChE and QNB binding in the AM contralateral to the injection did not change. However, the binding of aBuTX was found to decrease by approximately 40%. The present results suggest that the loss of CAT activity in the AM after treatment with KA is due to the destruction of cholinergic neurons within the AM. The lack of effect on AChE suggests that the major cholinergic input to the AM is not affected by KA. In addition, the loss of nicotinic receptors in the contralateral AM may reflect anterograde degeneration of terminals that have nicotinic sites located on them, or may be secondary to the elicitation of intense seizure activity evoked by the KA.
 ...
PMID:The effect of kainic acid on cholinergic enzymes and receptors in the amygdala complex of the rat. 740 18

We recently reported that systemic administration of the anticholinesterase, soman, caused rapid depletion of forebrain norepinephrine (NE) in convulsive but not in nonconvulsive rats. As neurons in nucleus locus coeruleus (LC) provide the bulk of NE innervation to most of the forebrain and the sole source of NE input to the cortex and the olfactory bulb, soman-induced NE depletion was hypothesized to result from activation of LC neurons. This activation was thought to be due to inhibition of acetylcholinesterase by soman, leading to rapid, sustained accumulation of acetylcholine in LC, causing these cells to fire at a high sustained rate. Support for this hypothesis was provided by neurophysiological findings showing that: (i) Systemic administration of soman in anesthetized rats caused a sustained, fivefold increase in the mean firing rate of LC neurons and (ii) microinjections of soman directly into LC caused a similar increase in the firing rate of LC neurons. Soman-induced activation of LC occurred prior to and even in the absence of seizures. As systemic administration of the muscarinic receptor antagonist, scopolamine, rapidly and completely reversed soman-induced activation of LC, it was further hypothesized that activation of LC neurons following soman administration is due to muscarinic receptor stimulation. The rapid release of NE by cholinolytic agents, thus, may play an important role in the initiation and/or maintenance of convulsions. To further test the hypothesis that NE release in soman-intoxicated rats is due to muscarinic activation of LC, we have investigated the effects of the muscarinic receptor agonist, pilocarpine, on NE release and LC discharge. In one set of experiments, rats were injected with a periconvulsive dose of pilocarpine (300 mg/kg, ip); both convulsive and nonconvulsive rats were sacrificed between 1 and 96 h and monoamine levels in the rostral forebrain and olfactory bulb were determined by HPLC with electrochemical detection. NE levels declined substantially only in convulsive rats; forebrain NE levels in convulsive rats rapidly decreased to 50% of control levels at 1 h and to 37% of controls level between 2 and 4 h. The time course and magnitude of these changes were similar to those observed following soman administration in our previous study. Recovery of forebrain NE began at 8 h and was complete by 96 h following pilocarpine administration. Neither dopamine (DA) nor serotonin (5-HT) levels were changed in the forebrain and olfactory bulb of either convulsive or nonconvulsive rats.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Pilocarpine-induced convulsions in rats: evidence for muscarinic receptor-mediated activation of locus coeruleus and norepinephrine release in cholinolytic seizure development. 768 35


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>